Hemorrhagic cystitis (HC) is a common complication following high-dose chemotherapy and bone marrow transplantation, and the treatment of virus-associated.
Bone Marrow Transplantation (2000) 26, 347–350 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt
Case report Treatment of BK virus-associated hemorrhagic cystitis and simultaneous CMV reactivation with cidofovir TK Held1, SS Biel2, A Nitsche1, A Kurth2, S Chen1,3, HR Gelderblom2 and W Siegert1 1
Klinik fu¨r Innere Medizin mit Schwerpunkt Ha¨matologie und Onkologie, Charite´/Campus Virchow-Klinikum; 2Robert Koch-Institut, Berlin, Germany; and 3Department of Internal Medicine, Ji-nan University Medical College, Guangzhou, China
Summary:
Case report
Hemorrhagic cystitis (HC) is a common complication following high-dose chemotherapy and bone marrow transplantation, and the treatment of virus-associated HC remains to be optimized. This is the first report on the successful use of cidofovir in a patient with HC and polyoma viruria concomitant with CMV reactivation after allogeneic BMT. Treatment led to a significant decrease in viruria and to sustained suppression of CMV reactivation. Administered with probenecid and hydration, cidofovir was well tolerated, and there were no side-effects. Bone Marrow Transplantation (2000) 26, 347–350. Keywords: BK virus; hemorrhagic cystitis; cidofovir; CMV reactivation
A 54-year-old Caucasian man with CML was transplanted in second chronic phase with bone marrow from an unrelated HLA-identical donor. Pretransplant therapy included fludarabine 30 mg/m2 i.v. once daily for 6 consecutive days (total dose 180 mg/m2), busulphan 4 mg/kg p.o. in divided doses daily for 2 days (total dose 8 mg/kg), and rabbit antithymocyte globuline (Fresenius) 10 mg/kg i.v. once daily for 4 consecutive days (total dose 40 mg/kg).7 CMV serology (IgG) of both donor and recipient was positive. GVHD prophylaxis consisted of cyclosporin A from day −1 onwards. On day +5, the patient observed some small blood clots in his urine, which were attributed to concurrent thrombocytopenia. The next day, the hematuria resolved spontaneously and was not noticed until day +16, when a second episode of microhematuria was seen lasting for 3 days. Acute grade II GVHD of the skin developed on day +19 and was treated with methylprednisolone (starting at 2 mg/kg daily p.o. in two doses with subsequent taper). GVHD resolved uneventfully within 3 weeks. Engraftment of leukocytes (⬎1000/l) was noted on day +14, and of platelets (⬎25 000/l) on day +16, respectively. On day +42, however, severe macrohematuria recurred together with severe dysuria and voiding frequency of 15 times a day. On ultrasound examination, the patient showed urinary retention as well as thickening of the bladder wall. Increased hydration provided no improvement. Polyomavirus was detected in the urine by electron microscopy and found to be BK virus when typed by seminested PCR (see below). Since his tests for CMV antigen (by APAAP) and CMV DNA (by PCR) became positive at the same time, we decided to treat him with cidofovir since this compound is known to have high antiviral activity against CMV and polyoma viruses too. On day +47, cidofovir was given at a dose of 5 mg/kg as a single infusion over 1 h. Simultaneously, probenecid and hydration were given p.o. and i.v., respectively, as recommended by the manufacturer. Cidofovir was administered again on days +54 and +67. In addition, estriol was given at a dose of 12 mg/day in three divided doses to control bladder bleeding.8 From day +45 to +72, urine was monitored daily for the presence of polyomavirus by electron microscopy, and virus was typed by seminested PCR and quantitated by TaqMan technology (see below). BK viruria (as assessed by electron
Hemorrhagic cystitis (HC) is a common complication following high-dose chemotherapy and bone marrow transplantation.1 Although seldom life-threatening, HC may cause significant morbidity. Its cause is attributed to the use of drugs such as oxazaphosphorines and busulfan1 or to viral infection with adeno-2 and polyomaviruses,3 but is still not definitively clear. The treatment of virus-associated HC remains to be optimized. Besides hydration and forced diuresis, there is no widely accepted treatment.1 There have been attempts made with antiviral medication4 as well as anti-inflammatory local therapy.5 Cidofovir is a cytidine nucleoside analogue recently licensed as an intravenous treatment for CMV retinitis in AIDS patients. It is, however, also the most active of several compounds tested against polyomaviruses such as BK virus and JC virus, respectively.6 Here, we describe the successful use of cidofovir in a patient with reactivated CMV infection and severe HC associated with polyomavirus (BK).
Correspondence: Dr W Siegert, Bone Marrow Transplant Unit, Klinik fu¨r Innere Medizin mit Schwerpunkt Ha¨matologie und Onkologie, Charite´/Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany Received 1 February 2000; accepted 16 April 2000
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microscopy) as well as numbers of virus copies (as assessed by PCR) started to decline on day +54, and reduced by more than two logs in number, respectively, on day +60 (Figure 1). Shortly thereafter, the patient’s hematuria started to improve, and his dysuria and frequency of voiding decreased (Figure 1). On day +80, he was discharged without signs or symptoms of HC. At follow-up visits, up to 6 months after BMT, he reported no signs or symptoms in this regard. By seminested PCR, no JC virus could be detected during the entire observation period. The patient was monitored on a weekly basis for the presence of CMV antigen and CMV-DNA in the peripheral blood. At day +72 (ie 27 days after treatment with cidofovir was started, his antigenemia resolved, and CMV-DNA became undetectable (Figure 1). Up to the last follow-up (day +355), CMV reactivation could not be demonstrated. During the entire post-transplantation period, results of the patient’s coagulation tests (partial thromboplastin time, prothrombin time) were constantly within normal ranges,
Polyomavirus genome equivalents/ml urine
1010
a
109 108 107
b
Polyomavirus particle
+++
Degree of hematuria CMV genome equivalents /ml plasma
Materials and methods Viral investigations were as follows. Fresh specimens of mid-stream urine were obtained every morning and were investigated for blood by microscopy and urine dipstick. Electron microscopy and PCR studies were also undertaken. For EM investigation, the urine was processed as described elsewhere.9 PCR was carried out on diluted crude urine as described elsewhere.10 For real-time quantification, a Taqman assay with a general set of primers and exonuclease probe specific for human polyomavirus BK and JC was used. The concentration of viral genome was determined by correlation to a calibration curve derived from serial plasmid dilutions in urine. For differentiation between BKV and JCV, a seminested PCR assay was used, producing different amplicon sizes for BKV (246 bp) and JCV (199 bp), respectively.
++
Discussion
+
c
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CMV antigen positive cells/10 000 WBC
and the number of platelets did not fall below 25 000/l after engraftment. His creatinine clearance before BMT was 80 ml/min as estimated by the Cockroft–Gault equation. His serum creatinine was elevated up to 1.8 mg/dl (normal range, ⬍1.3 mg/dl) on day +4 and on some occasions thereafter (days +18 to +21, days +82, +96, and +103), but never exceeded 1.6 mg/dl and always returned to normal levels spontaneously. From day +103, no elevated serum creatinine levels were observed on bimonthly controls.
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d
104 103 102 101
e
4 3 2 1 0
40
45
50
55
60
65
70
75
Days after BMT Figure 1 Course of BK virus viruria, hematuria, and CMV reactivation in a patient with simultaneous CMV reactivation and hemorrhagic cystitis. (a) Number of BK virus genomic equivalents per ml of urine; (b) degree of BK viruria; (c) degree of hematuria; (d) degree of CMV viremia; and (e) degree of CMV antigenemia. The triangles in each panel denote the time of cidofovir treatment. Bone Marrow Transplantation
HC is a common complication after BMT, its frequency being reported to be from about 6.4%11 to more than 30%.12 Age and use of cyclophosphamide or busulfan in conditioning regimens13 are recognized risk factors for developing HC. Also, HC is frequently associated with infections by adeno- and polyomaviruses.3,14 In this patient, we assume BK virus was the main cause of the cystitis because he had a high level of viruria as demonstrated by two independent methods and because treatment with cidofovir, known to have high activity against polyomavirus in vitro,6 lowered his viruria significantly. In addition, he showed evidence of CMV reactivation. Since CMV has been isolated from the urine of patients with HC,15 this reactivation could have contributed to our patient’s cystitis. There are previous reports describing treatment of HC with various antiviral drugs. Adenovirus-associated HC has been treated with ganciclovir,16 as well as with ribavirin being either effective17 or ineffective.18 Adenovirus-associated and polyomavirus-associated HC has also been treated with vidarabine with good effect on viruria and a moderate effect on clinical symptoms.4 Cidofovir has been used to date to treat CMV infection and reactivation unresponsive to ganciclovir or foscarnet (reviewed in Ref 19). Simultaneous treatment with cidofovir of BK virus-associated HC and CMV reactivation has not been described, however. We chose this approach since our patient had both BK viruria and HC, as well as evidence of CMV reactivation,
Treatment with cidofovir of BK virus-associated HC TK Held et al
concurrently. As assessed by electron microscopy and quantitative PCR for BK viruria and by established techniques for CMV viremia, this treatment was effective in our patient. Since antiviral activity of cidofovir against CMV is high in the urine,19 it is possible that its antiviral activity against BK virus is also maintained, thus contributing to the decrease of BK virus viruria observed in our patient. Interestingly, cidofovir itself caused HC as a side-effect in two of 28 patients treated for CMV disease.20 In the same abstract, it was reported that cidofovir was administered to one patient with polyomavirus infection with HC, but no data about the efficacy of this treatment are given. The debate about a causal role of polyomavirus infection in HC is still open. Arguments against this role include studies showing that primary BK virus infection was not the cause of HC after BMT in children.21 Also, an association between the presence of a specific human polyomavirus in blood and HC could not be observed in either allogeneic or autologous BMT patients.22 On the other hand, T celldepletion of bone marrow before transplantation was significantly associated with adeno- and polyomavirusinduced HC.23 Moreover, in a study well-controlled for amelioration of toxic effects of cyclophosphamide, there were no cases of HC in patients who did not excrete BK virus, but 50% of patients with persistent BK viruria had HC.24 In addition, the temporal correlation of onset of BK viruria and onset of HC was highly significant.24 Although we did not perform serial bladder biopsies to investigate the presence of BK virus in tissue samples, the time relationship between specific treatment against BK virus and decreasing viruria adds to the evidence that infection with BK virus could be responsible for at least some cases of HC after BMT. In conclusion, this is the first report of the successful use of cidofovir in a patient with HC and polyoma viruria concomitant with CMV reactivation. Treatment led to a significant decrease in viruria and to sustained suppression of CMV reactivation. Administered together with probenecid and hydration, cidofovir was well tolerated by the patient, and there were no side-effects. Clinical trials of cidofovir in HC associated with polyoma- or adenovirus are clearly warranted. Acknowledgements
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We express our gratitude to the nursing and medical staff of our BMT unit who cared excellently for our patient. 19
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